Fungal Allergens Trigger Innate Type 2 Airway Inflammation via Protease-Mediated Barrier Disruption

Inhaled exposure to fungal spores is strongly associated with severe asthma and chronic rhinosinusitis (CRS), often presenting with more severe endotypes compared to other triggers. A critical gap exists in fully understanding the precise mechanisms by which these ubiquitous fungi, particularly Alternaria and Aspergillus species, elicit a robust innate immune response that drives type 2 inflammation. This mechanistic gap hinders the development of targeted therapeutic strategies for fungal-associated airway diseases, which are characterized by epithelial barrier disruption and the release of alarmin cytokines.

This review systematically synthesized current literature on innate airway immune responses to fungal allergens, aiming to detail the underlying mechanisms. The authors focused on identifying how common fungi, including Alternaria, Aspergillus, Cladosporium, Penicillium, and Candida, trigger inflammation. Specific attention was given to the roles of fungal protease activity, epithelial barrier disruption, and the subsequent release of alarmin cytokines. The review consolidated understanding of type 2 inflammatory pathways and highlighted areas for future research and therapeutic development.

The review highlights that ubiquitous fungi, particularly Alternaria and Aspergillus species, are primary drivers of severe asthma and CRS through robust innate immune responses. Fungal proteases were identified as key initiators, directly disrupting airway mucosal barriers and activating protease-activated receptors (PARs). This activation leads to the release of alarmin cytokines, including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), which are central to driving innate type 2 inflammatory responses.

Recent studies show protease allergens can cleave the protease-sensing domain of IL-33, generating a more active form that amplifies inflammation. These alarmins subsequently activate innate immune cells such as group 2 innate lymphoid cells (ILC2s), dendritic cells, mast cells, and eosinophils, collectively contributing to epithelial mucus production, airway hyperresponsiveness, and tissue remodeling characteristic of severe allergic airway disease.